Adhesion G protein-coupled receptor Gpr126/Adgrg6 is essential for placental development.

Mutations in the G protein–coupled receptor GPR126/ADGRG6 cause human diseases, including defective peripheral nervous system (PNS) myelination. To study GPR126 function, we generated new genetic mice and zebrafish models. Murine Gpr126 is expressed in developing heart endocardium, and global Gpr126 inactivation is embryonically lethal, with mutants having thin-walled ventricles but unaffected heart patterning or maturation. Endocardial-specific Gpr126 deletion does not affect heart development or function, and transgenic endocardial GPR126 expression fails to rescue lethality in Gpr126-null mice. Zebrafish gpr126 mutants display unaffected heart development. Gpr126 is also expressed in placental trophoblast giant cells. Gpr126-null mice with a heterozygous placenta survive but exhibit GPR126-defective PNS phenotype. In contrast, Gpr126-null embryos with homozygous mutant placenta die but are rescued by placental GPR126 expression. Gpr126-deficient placentas display down-regulation of preeclampsia markers Mmp9, Cts7, and Cts8. We propose that the placenta-heart axis accounts for heart abnormalities secondary to placental defects in Gpr126 mutants.This study was supported by grants PID2019-104776RB-I00, CB16/11/00399 (CIBER CV), and RD16/0011/0021 (TERCEL) from the MCIN/AEI/10.13039/501100011033 and a grant from the Fundación BBVA (ref. BIO14_298) to J.L.d.l.P. D.Y.R.S. was funded by the Max Planck Society and the European Research Council, ERC AdG 694455-ZMOD. R.T.-C. was supported by a PhD fellowship from Fundación “La Caixa” (ref. LCF/BQ/ES15/10360023), an EMBO short-term fellowship (ref. 7684), “Ayudas para Estancias Breves en España y en el Extranjero para Personal Docente e Investigador en Formación de la UAM,” and a Boehringer Ingelheim Fonds travel grant. J.G.-B. was funded by Programa de Atracción de Talento from Comunidad de Madrid (ref. 2016 T1/BMD1540).The cost of this publication was supported, in part, with funds from the European Regional Development Fund. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the MCIN, and the Pro CNIC Foundation.S